Experimental Compound for FA Hits Its Molecular Target

Scientists at the Scripps Research Institute in La Jolla, Calif., and the Repligen Corporation in Waltham, Mass., have identified the precise biochemical brake that limits production of a needed protein in Friedreich's ataxia (FA) and determined that this brake is specifically targeted by an experimental compound being developed to treat this disease. MDA is supporting Repligen to develop this drug.

About Friedreich's ataxia

Friedreich's ataxia is caused by a lack of the frataxin protein. FA is characterized by incoordination (ataxia), severe weakness and cardiac muscle deterioration.

Normally, the frataxin gene contains five to 30 repeated sequences of the DNA nucleotides guanine, adenine and another adenine (GAA). However, in people with FA, the gene contains hundreds to thousands of these GAA repeats.

When the frataxin gene contains the extra GAAs, proteins called histones that stick to the DNA lose a chemical flag called an acetyl group. An acetyl flag tells the cell that the DNA is "open" and can be used as a set of instructions for the frataxin protein. Without the acetyl flag, the gene is interpreted by the cell as "closed" or "silent."

About the new findings

Until now, the precise mechanism by which the acetyl flag is lost in FA has not been clear, although researchers have been fairly certain that the flag is removed by the action of enzymes called histone deacetylases (HDACs).

Joel Gottesfeld at the Scripps Research Institute, in whose lab the Repligen compound originally was developed, published the new findings Sept. 25, 2009, in Chemistry & Biology, with colleagues Chunping Xu at Scripps, MDA grantee James Rusche at Repligen, and others.

The findings show that a particular HDAC called HDAC3 is responsible for removing the flags, silencing the expanded frataxin genes, and severely limiting frataxin production in FA.

They also show that an HDAC inhibitor being developed by Repligen to treat FA specifically targets HDAC3.

In frataxin-deficient mice with a disease resembling FA, the new HDAC inhibitor increased levels of frataxin RNA in the brain and heart, two of the organs most affected by the disease. There were no acute or chronic toxic effects in the mice.

Meaning for people with FA

The finding that Repligen's experimental compound for FA hits the specific enzyme that prevents adequate frataxin production and apparently has minimal effects on other targets supports its development as a medication for this disease and improves the likelihood that it will be safe and effective.

Other HDAC inhibitors are not as specific in their targets and can be highly toxic.

The drug must be tested in human trials before it can be approved by the U.S. Food and Drug Administration for use by people with FA.